Malaria increases the risk of severe anemia, spontaneous abortion and fetal death in pregnant women; and low birth weight, anemia, poor developmental outcomes and mortality in their infants. These complications of malaria are amplified in the setting of HIV infection. The use of insecticide treated nets (ITNs) and antifolate therapy can reduce the malaria associated morbidity in pregnant women, but the protection afforded by these interventions is far from complete. We propose to test the hypothesis that the strategic use of HIV protease inhibitors (Pl)s during pregnancy and breastfeeding of HIV-infected women will improve maternal and infant outcomes. This hypothesis is based on the appreciation that malaria parasites and HIV express biochemically similar proteases and the observation by our group and others that HIV Pis exert potent in vitro antimalarial activity. Study aims are: 1) To determine if Pi-based antiretroviral therapy (ART) decreases the risk of poor obstetric and infant outcomes among HIV -infected pregnant women as compared to non-PI-based ART; 2) To compare the maternal and infant safety and tolerability profiles of PI versus non-Pi based ART during pregnancy and breastfeeding; 3) To compare the virologic and immunologic efficacy of PI versus non-Pi based ART during pregnancy and breastfeeding. To address these aims, we will conduct a randomized, open-label, trial of PI (lopinavir/ritonavir) vs. non- PI-based antiretroviral therapy among 500 HIV- infected women up to 28 weeks gestation. Women and infants will be followed through 6 months of lactation. The primary study endpoint will be the risk of placental malaria. Secondary endpoints will include a composite of infant low birth weight (<2500 g), fetal death and late spontaneous abortion. The study will be conducted in the Tororo district, Uganda, an area of high malaria transmission. It will be conducted in the context of a public health framework of proven preventive strategies that are currently the standard of care for most of sub-Saharan Africa; chemoprophylaxis with trimethoprim-sulfamethoxazole and ITNs. Our goal is to reduce the burden of HIV and malaria and to improve maternal and infant outcomes.